Molecular Pathways

Targeting TRAIL Agonistic Receptors for Therapy Carmelo Carlo-Stella,1, 3 Cristiana Lavazza,1, 3 Alberta Locatelli,2 Lucia Vigano' ,2 Alessandro M. Gianni,1, 3 and Luca Gianni2

Abstract Basedonpreclinical studies demonstrating that tumornecrosis factor ^ relatedapoptosis-inducing ligand (TRAIL) exerts a potent and cancer ^ specific proapoptotic activity, recombinant TRAIL as well as agonistic anti ^ TRAIL-R1and anti ^ TRAIL-R2 recently entered clinical trials. Additionally, therapy approaches usingTRAIL-encoding adenovirus (Ad-TRAIL) are currently being developed to overcome the limitations inherent toTRAIL receptor targeting, i.e., pharmacokinetic of solubleTRAIL, pattern of receptor expression, and tumor cell resistance. To optimize gene therapy approaches, CD34+ cells transduced with Ad-TRAIL (CD34-TRAIL+)have been investigated as cellular vehicles forTRAIL delivery. Transduced cells exhibit a potent tumor killing activity on a variety of tumor cell types both and in vivo and are also cytotoxic against tumor cells resistant to solubleTRAIL. Studies in tumor-bearing nonobese diabetic/severe combined immunodeficient mice suggest that the antitumor effect of CD34-TRAIL+ cells is medi- ated by both direct tumor cell killing due to and indirect tumor cell killing due to vascular- disrupting mechanisms. The clinical translation of cell and gene therapy approaches represent a challenging strategy that might achieve systemic tumor targeting and increased intratumor deliv- ery of the therapeutic agent.

Background (TRAIL), stand out because of their ability to induce cell death (5, 6). Dysregulated apoptosis plays a key role in the pathogenesis TRAIL, in its soluble form, is emerging as an attractive and progression of neoplastic disorders, allowing tumor cells anticancer agent because of its cancer cell specificity and potent to survive beyond their normal life span and to eventually antitumor activity. In vitro several sets of evidence show that acquire chemoradioresistance (1, 2). Thus, apoptotic pathways TRAIL selectively induces apoptosis in a variety of transformed represent attractive therapeutic targets for restoring apoptosis cell lines (7–9); in vivo administration of TRAIL to mice exerts a sensitivity of malignant cells or activating agonists of remarkable activity against tumor xenografts of various apoptosis. To modulate apoptotic and , several (10–15). Unlike other apoptosis-inducing TNF family mem- strategies can be envisaged that target either the mitochondria- bers, soluble TRAIL seems to be inactive against normal healthy dependent (intrinsic) or the death receptor-dependent (extrin- tissue (10), and reports in which TRAIL induces apoptosis in sic) pathways of apoptosis (3). Because of the ability of death normal cells could be attributed to the specific preparations of receptor ligands to induce death in susceptible cell types, there TRAIL used in the experiments (16). The physiologic functions has been considerable interest in the physiologic roles and of TRAIL are not yet fully understood, but mouse gene knock- therapeutic potential of these as anticancer agents. out studies indicate that this agent has an important role in Death receptor ligands of the tumor factor a (TNFa) antitumor surveillance by immune cells, mediates thymocyte superfamily are type II transmembrane proteins that signal to apoptosis, and is important in the induction of autoimmune target cells on cell-cell contact, or after protease-mediated (17–19). TRAIL signals by interacting with its receptors. release to the extracellular space (4). Four members of this Thus far, five receptors have been identified, namely, the two family, namely, , TNFa, TL1A (a recently discovered agonistic receptors, TRAIL-R1 (20) and TRAIL-R2 (21), and the TNF-like ligand), and TNF–related apoptosis-inducing ligand three antagonistic receptors (22) TRAIL-R3 (23), TRAIL-R4 (24), and osteoprotegerin (OPG; ref. 25). Both TRAIL-R1 and TRAIL- R2 are type I transmembrane proteins containing a cytoplasmic death domain (DD) motif that engage apoptotic machinery Authors’ Affiliations: 1‘‘Cristina Gandini’’ Medical Oncology Unit and 2Medical upon ligand binding (7), whereas the other three receptors Oncology 1, Istituto NazionaleTumori, and 3Medical Oncology, University of Milan, either act as decoys or transduce antiapoptotic signals (26). Milan, Italy TRAIL-R3 and TRAIL-R4 have close homology to the extracel- Received 11/22/06; revised 12/4/06; accepted12/14/06. Grant support: Ministero dell’Universita' e della Ricerca (MUR, Rome, Italy), lular domains of agonistic receptors. TRAIL-R4 has a truncated, Ministero della Salute (Rome, Italy), and Michelangelo Foundation for Advances in nonfunctional cytoplasmic DD, whereas TRAIL-R3 exists on the Cancer Research andTreatment (Milan, Italy). plasma membrane as a glycophospholipid-anchored Requests for reprints: Alessandro M. Gianni,‘‘Cristina Gandini’’Medical Oncology lacking the cytosolic tail. The physiologic relevance of OPG as a Unit, Istituto Nazionale Tumori, Via Venezian, 1-20133 Milan, Italy. Phone: 39-2- 2390-2532; Fax: 39-2-2390-3461;E-mail: [email protected]. soluble receptor for TRAIL is unclear, but a recent study suggests F 2007 American Association for Cancer Research. that cancer-derived OPG may be an important survival factor in doi:10.1158/1078-0432.CCR-06-2774 hormone-resistant prostate cancer cells (27).

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TRAIL-Induced Apoptosis Signaling (Bax) and/or the loosely bound mitochondrial homologue Bcl- 2 antagonist/killer (Bak) to insert into the mitochondrial TRAIL forms homotrimers that bind three receptor mole- membrane, where they contribute to the mitochondrial release cules, each at the interface between two of its subunits. A Zn of cytochrome c (30). In the cytosol, cytochrome c binds the atom bound to cysteine residues in the trimeric ligand is adaptor protein apoptotic protease activating factor 1 (Apaf-1) essential for trimer stability and optimal biological activity. to form an apoptosome with recruitment and activation of the Binding of TRAIL to the extracellular domain of agonistic apoptosis-initiating -9, which proteolytically activates receptors results in the trimerization of the receptors and additional caspase-3. These events are further amplified by clustering of the intracellular DDs, which leads to the apoptogenic factors released from the mitochondrial space, recruitment of the adaptor molecule Fas-associated protein including Smac/DIABLO [second mitochondrial activator of with death domain (FADD; Fig. 1). Subsequently, FADD /direct IAP-binding protein with low isoelectric point recruits initiator caspase-8 and caspase-10, leading to the (pI)], which displaces the X-chromosome–linked inhibitor of formation of the death-inducing signaling complex (DISC), in apoptosis protein (XIAP) from caspase-3, caspase-7, and which initiator caspases autoactivate by proteolysis. Once they caspase-9 (31). become enzymatically active, caspase-8 and/or caspase-10 are released from the DISC and signal through two different Clinical-Translational Advances proteolytic pathways that converge on caspase-3 and lead to cellular disassembly (28). In type I cells, activation of initiator Apoptosis induction in response to most DNA-damaging caspases upon death receptor ligation is sufficient to directly drugs usually requires the function of the tumor suppressor activate downstream effector caspases, such as caspase-3 and/or , which engages primarily the intrinsic apoptotic-signaling caspase-7 (29). This extrinsic pathway is independent of the pathway. In most human cancers, however, tumor progression mitochondria and is not blocked by overexpression of Bcl-2. In as well as conventional treatments eventually select for tumor type II cells, the commitment from death receptor ligation to cells in which p53 is inactivated, resulting in resistance to apoptosis is less direct (29). The amount of initially cleaved therapy. Activation of the DD-containing TRAIL receptors caspase-8 and/or caspase-10 is not enough to directly trigger represents an opportunity to exploit the extrinsic apoptotic effector caspase activation. Consequently, apoptotic signaling pathway to destroy cancer cells, regardless of p53 status, and requires an amplification loop by mitochondrial pathway therefore, it might be a useful therapeutic strategy, particularly engagement through caspase-8–mediated cleavage of Bid in cells in which the p53-response pathway has been (BH3 interacting DD agonist), which, in turn, induces the inactivated, thus helping to circumvent resistance to chemo- cytosolic Bcl-2 family member Bcl-2–associated X protein and radiotherapy. Based on promising preclinical observations,

Fig.1. Crosstalk between apoptosis signaling pathways following activation of death receptors. Death receptors trigger the cell-intrinsic pathway by activation of caspase-8 and caspase-10. Cleaved BID interacts with Bax and Bak, which in turn, activate caspase-9 and caspase-3, resulting in apoptosis induction through the cell-extrinsic pathway. In type I cells, death-receptor engagement of the cell-extrinsic pathway is sufficient for commitment to apoptotic death. In type II cells, commitment to apoptosis requires the amplification of the death-receptor signal by the cell-intrinsic pathway. Because death-receptor targeting and conventional agents induce tumor cell apoptosis through different signaling pathways, combinations of the two approaches might facilitate the killing of tumor cells that resist death induction through either one of the pathways.

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Fig.2. Therapeutic approaches to death receptor activation. TRAIL-R1and TRAIL-R2 can be engaged by solubleTRAIL as well as the membrane-bound form of the ligand. Agonistic antibodies selectively bind either TRAIL-R1orTRAIL-R2.

recombinant TRAIL as well as agonistic anti–TRAIL-R1 and biological relevance of the decoy receptors, their ability to anti–TRAIL-R2 antibodies recently entered clinical trials inhibit TRAIL signaling, and the expression profile of the decoy (Fig. 2). receptors have not yet been fully investigated. Recombinant TRAIL, a receptor agonist that directly activates Tumor cells may have an impaired apoptotic response to both TRAIL-R1 and TRAIL-R2, is currently being codeveloped TRAIL because of resistance mechanism(s) occurring at by Genentech (San Francisco, CA) and Amgen (Thousand different points along the TRAIL signaling pathway (34). Oaks, CA) as a targeted therapy for solid tumors and Dysfunctions due to mutations and defects in either the death hematologic malignancies. Phase I studies using recombinant receptors TRAIL-R1 or TRAIL-R2, as well as the adaptor protein TRAIL have been initiated, but results are not yet available (32). FADD and caspase-8, can lead to TRAIL resistance because of HGS-ETR1 (Mapatumumab; Human Sciences, Rock- their essential role in the DISC complex assembly (20, 22–24). ville, MD) is a fully human agonistic monoclonal that Overexpression of cellular FADD-like interleukin-1h–convert- targets TRAIL-R1. HGS-ETR1 is currently in phase II clinical ing enzyme-inhibitory protein (cFLIP) correlates with TRAIL development as a single agent in patients with non–small cell resistance in several types of cancer. Overexpression of Bcl-2 or and colorectal cancer (reviewed in ref. 33). Clinical Bcl-XL, loss of Bax or Bak function, high expression of inhibitor activity of HGS-ETR1 is suggested by three partial responses of apoptosis proteins, and reduced release of Smac/DIABLO observed in a recently reported multicenter phase II trial in from the mitochondria to the cytosol have all been reported to relapsed non-Hodgkin lymphoma receiving either 3 or 10 mg/ result in TRAIL resistance in mitochondria-dependent type II kg HGS-ETR1 every 3 weeks for six cycles or until cancer cells (11, 12, 34). Finally, activation of different subunits progression (33). Additional phase Ib trials with HGS-ETR1 in of mitogen-activated protein kinases or nuclear factor-nB can combination with carboplatin/paclitaxel and cisplatin/gemci- lead to development of either TRAIL resistance or apoptosis in tabine have been initiated in patients with advanced solid certain types of cancer cells (22, 34). malignancies (33). Fully human antibodies to TRAIL-R2 (HGS- The mechanism(s) to overcome TRAIL resistance remains ETR2 and HGS-TR2J; Human Genome Sciences) have also largely unclear. A prolonged exposure to the drug or very high entered the clinic and are currently in phase I clinical doses of TRAIL might be required to overcome resistance development (33). Agonist monoclonal antibodies specifically (35–38). Because of the short half-life of TRAIL in plasma (10) bind and activate TRAIL-R1 (HGS-ETR1) or TRAIL-R2 and rapid elimination (15), however, achieving prolonged (HGSETR2 and HGS-TR2J). Monoclonal antibodies restrict exposure at high concentrations is difficult. Despite in vivo the therapeutic target to tumors with a distinct receptor studies using a trimerized (15) or a nontagged (10, 39) form of expression profile, whereas soluble TRAIL interacts with both TRAIL having shown a good toxicity profile of the molecule, TRAIL-R1 and TRAIL-R2 as well as the decoy receptors. organ toxicity might occur when using high doses of soluble Therefore, soluble TRAIL may either have a wider therapeutic TRAIL. In experimental anticancer treatments, the response spectrum or a narrower and more unpredictable therapeutic to TRAIL-induced apoptosis was significantly increased on window compared with the highly specific antibodies. The coadministration of DNA-damaging chemotherapeutic drugs

www.aacrjournals.org 2315 Clin Cancer Res 2007;13(8) April 15, 2007 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2007 American Association for Cancer Research. Molecular Pathways because of up-regulation of TRAIL-R1 and/or TRAIL-R2 (40, 41). of triggering apoptosis more efficiently than soluble TRAIL and In addition, irradiation seems to specifically up-regulate TRAIL- overcoming tumor resistance to the soluble ligand. This R2 receptor expression, and combining irradiation with TRAIL peculiar functional property of mTRAIL might be due to a treatment has an additive or synergistic effect (42). Alternatively, differential activation of TRAIL-R1 and TRAIL-R2 by soluble up-regulation of TRAIL-R1 or TRAIL-R2 using small molecules, and membrane TRAIL as suggested by studies showing that such as the inhibitor bortezomib (43) or inhibitors TRAIL-R1 signals apoptosis on triggering by both the soluble of deacetylase (44) might allow to overcome TRAIL and membrane-bound form of the ligand, whereas TRAIL-R2 resistance. becomes only activated by mTRAIL or soluble TRAIL cross- Several gene therapy approaches are currently being devel- linked by antibodies (56, 57). CD34-TRAIL+ cells also showed oped to specifically target tumor cells and overcome the potent in vivo tumoricidal efficacy in nonobese diabetic/severe limitations inherent to death receptor targeting, i.e., pharma- combined immunodeficient (NOD/SCID) mice xenografted cokinetic, toxicity profile, pattern of receptor expression, tumor with soluble TRAIL-sensitive and TRAIL-resistant tumors. cell resistance. A TRAIL-expressing adenoviral vector (Ad- Repeated dosing with mTRAIL-armed cells resulted in a TRAIL) has been recently shown to cause direct tumor cell significantly prolonged survival of tumor-bearing mice (51). killing, as well as a potent bystander effect through the Histologic analysis of tumor nodules growing in vivo in NOD/ presentation of TRAIL by transduced normal cells (45). Using SCID mice showed an efficient tumor homing of transduced Ad-TRAIL might be an alternative to delivery of systemic soluble cells and a high level of expression of the agonistic TRAIL-R2 TRAIL that may lead to better tumor cell targeting and increased receptor by tumor endothelial cells (51). Indeed, injection of tumoricidal activity (45–49). Optimal Ad-TRAIL–based gene CD34-TRAIL+ cells resulted in extensive damage of the tumor therapy, however, requires efficient infection of target tumor vasculature followed by hemorrhagic necrosis that exhibited a cells and avoidance of immune clearance (50). In addition, perivascular distribution, suggesting that CD34-TRAIL+ cells safety and toxicity issues linked to the systemic vector might be an efficient vehicle for mTRAIL delivery to tumors, administration force cancer researchers to adopt an intra- where they exert a potent antitumor effect mediated by both tumoral injection of Ad-TRAIL, which results in local therapeu- direct tumor cell killing due to apoptosis and indirect tumor tic activity with limited value for treating disseminated tumors. cell killing due to vascular-disrupting mechanisms. To optimize the use of TRAIL-encoding adenovectors, Because death receptor activation can instruct malignant cells thereby allowing the systemic delivery of TRAIL, we explored to undergo apoptosis independent of p53, targeting death and recently described a cell therapy approach using a receptors with TRAIL-targeting therapeutics is a rational replication-deficient Ad-TRAIL encoding a full-length mem- therapeutic strategy against cancer. According to experimental brane-bound TRAIL (mTRAIL) to transduce CD34+ cells data obtained thus far, TRAIL-targeting therapeutics possess (CD34-TRAIL+; ref. 51; Fig. 2). Gene-modified CD34+ cells considerable and specific antitumor therapeutic activity both represent optimal vehicles of antitumor molecules. In fact, they when used alone as well as in combination with nonspecific can migrate from the bloodstream into tumor tissues because of cytotoxic agents, radiation, and other target-based therapeutics. the expression of adhesion receptors that specifically interact In a way that recapitulates the dilemmas faced with targeted with counter-receptors on endothelial cells in the tumor agents in clinical development, the ideal tumor types to select microenvironment (52–54). Additionally, up-regulation of to achieve a proof of principle of clinical activity of TRAIL inflammatory chemoattractants in the tumor microenviron- receptor targeting is not known. TRAIL-targeting therapeutics ment provides a permissive environment that allows for are highly specific for the TRAIL death receptors. Therefore, the homing of systemically delivered CD34-TRAIL+ cells and level of receptor expression should be evaluated in clinical efficient tumor targeting (55). In vitro CD34-TRAIL+ cells specimens as a prerequisite for patient’s inclusion in clinical exhibited high killing activity on a variety of tumor cell types, studies. Clinical translation of gene therapy approaches using including lymphoma, multiple myeloma, as well as epithelial adenovector-transduced cells for delivery of membrane-bound cancers, and most importantly, mTRAIL-armed cells were TRAIL represent a challenging strategy that might achieve highly cytotoxic against tumor cells resistant to soluble TRAIL systemic tumor targeting and increased intratumor delivery of (51). Thus, the membrane-bound form of the ligand is capable the therapeutic agent.

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Carmelo Carlo-Stella, Cristiana Lavazza, Alberta Locatelli, et al.

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